Protein Supplementation in Hyponatremia Due to the Syndrome of Inappropriate Antidiuresis (TREASUREx)

Effect of Protein Supplementation in Hospitalized Patients With Hyponatremia Due to the Syndrome of Inappropriate Antidiuresis - a Monocentric Randomized Open-label Pragmatic Active-controlled Trial - the TREASUREx Trial

The goal of this study is to assess the impact of protein supplementation on hyponatremia caused by the syndrome of inappropriate antidiuresis during hospitalization.

Study Overview

• Status: Recruiting
• Conditions: Hyponatremia; Syndrome of Inappropriate Antidiuresis
• Intervention / Treatment: Dietary supplement: Moltein PURE Protein Powder; Behavioral: Fluid restriction

Detailed Description

Hyponatremia (plasma sodium <135 mmol/L) is the most common electrolyte disorder, affecting up to 30% of hospitalized patients. Chronic hyponatremia (>48 hours) is linked to longer hospital stays, higher costs, increased mortality, and morbidity (e.g., falls, fractures, cognitive deficits). The most common cause of euvolemic hyponatremia is syndrome of inappropriate antidiuresis (SIAD), characterized by excessive water retention due to dysregulated vasopressin activity. Treatment options include fluid restriction or increasing water excretion with AVP antagonists, SGLT2 inhibitors, or oral urea.

A recent trial showed that protein supplementation can induce osmotic diuresis and raise sodium levels similarly to oral urea, with better tolerability. Since protein supplementation is often used in hospitalized patients with malnutrition, this study aims to compare its acceptability to fluid restriction in hospitalized SIAD patients. This head-to-head superiority trial will randomize patients to receive either 80 g of dietary protein daily or fluid restriction (1000 mL/day) for up to 5 days. The hypothesis is that protein supplementation is significantly more acceptable to patients than fluid restriction, ultimately improving treatment outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mirjam Christ-Crain, Prof. MD; Phone Number: +41 61 328 70 80; Email: mirjam.christ-crain@usb.ch
• Study Contact Backup: Name: Cemile Bathelt; Phone Number: +41 61 556 54 07; Email: cemile.bathelt@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel
    • Contact: Mirjam Christ-Crain; Phone Number: +41 61 328 70 80; Email: mirjam.christ-crain@usb.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients with confirmed SIAD during the hospital stay or at screening, defined by:
• Plasma sodium concentration <135 mmol/L
• Plasma osmolality <300 mOsm/kg
• Urine osmolality >100 mOsm/kg
• Urine sodium concentration >30 mmol/L
• Clinical euvolemia (no signs of hypovolemia or hypervolemia)

Exclusion Criteria:

• Lactose intolerance, milk protein allergy, soy allergy, nuts allergy, or hypersensitivity to components of the protein supplement.
• Inborn metabolic disorders affecting carbohydrate, lipid, or protein metabolism.
• Severe symptomatic hyponatremia requiring 3% NaCl or intensive care.
• New (within the last five days) treatment with SGLT2 inhibitors, vaptans or oral urea
• Uncontrolled severe hypothyroidism (untreated)
• Uncontrolled adrenal insufficiency (morning cortisol <150nmol/l)
• eGFR <45 mL/min/1.73 m² (KDIGO G3b-5) or end-stage renal disease (dialysis)
• Severe hepatic impairment or advanced symptomatic liver disease defined as past or current hepatic encephalopathy, liver cirrhosis Child C, or decompensated (bleeding, jaundice, hepatorenal syndrome)
• Pregnancy, breastfeeding, or plans to become pregnant during the study.
• End-of-life care
• Lack of capacity or other reasons preventing from giving informed consent or following study procedures (e.g., due to language problems, psychological disorders, dementia, etc.)
• Treatment with thiazid diuretic (must be stopped at least 48 hours before inclusion)

Post-randomization Exclusion Criteria:

• Type 1 diabetes or uncontrolled type 2 diabetes (HbA1c >8.0%)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Protein Supplementation; 80 g protein supplementation per day (two bottles, each containing 40 g protein)	Dietary supplement: Moltein PURE Protein Powder; 80 g protein supplementation per day (two bottles, each containing 40 g protein)
Active Comparator: Fluid restriction; total daily fluid intake to a maximum of 1000 ml	Behavioral: Fluid restriction; total daily fluid intake to a maximum of 1000 ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of Intervention Measure (AIM) questionnaire	Treatment acceptability is assessed using the Acceptability of Intervention Measure (AIM) questionnaire, a validated patient-reported outcome measure scored on a 1 to 5 Likert scale. The total AIM score ranges from 4 to 20, with higher scores indicating greater acceptability. The primary analysis will compare AIM scores between the two treatment groups at the end of the intervention (day 5 or discharge).	On day 5 (or discharge)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma sodium levels	Change in change in plasma sodium levels in mmol/l will be assessed at study inclusion to day 5 of treatment or until discharge	Daily measurements from the day of inclusion to day 5
Estimated glomerular filtration rate (eGFR)	Assessement of creatinine levels	On the day of inclusion and on day 5
Changes in blood electrolytes	Assessement of sodium levels	On the day of inclusion and on day 5
Changes in urine electrolytes	Assessement of sodium levels	On the day of inclusion and on day 5
Changes in glucose levels	Assessement of glucose levels	On the day of inclusion and on day 5
Changes kidney parameters	Assessement of urea and uric acid levels	On the day of inclusion and on day 5
Plasma sodium levels one day after treatment start	Plasma sodium levels 12-36 hours after treatment start in patients with a plasma sodium concentration <125 mmol/L at baseline.	On the day of inclusion and 12-36 hours after treatment initiation
Endocrine parameters	Blood levels of copeptin, aldosterone, renin, MR-proANP and NT-proBNP, apelin, etc. are assessed	On the day of inclusion and on day 5
Symptoms of hyponatremia	Symptoms of hyponatremia (e.g. vertigo, headache, nausea, attention deficit, mental slowness, forgetfulness, gait instability) assessed by a questionnaire (yes/no; if yes: VAS, 0-10).	On the day of inclusion and on day 5
Fluid intake	Oral daily fluid intake assessed using a self-completed drinking protocol.	Daily measurements from the day of inclusion to day 5
Changes in body weight	Body weight is assessed	On the day of inclusion and on day 5
Changes in blood pressure	Systolic and diastolic blood pressure will be measured	On the day of inclusion and on day 5
Changes in heart rate	Heart rate will be assessed	On the day of inclusion and on day 5
Differences in clinical outcomes - length of hospital stays	Length of hospital stays will be assessed	Daily from the day of inclusion to day 5
Need for additional hyponatremia treatment and treatment escalation	Assessment of treatment escalation (YES/NO) including: A: administration of 3% NaCl infusion; B: administration of oral urea; C administration of SGLT2 inhibitors; D: administration of vaptans; E: administration of diuretics; F: other during the treatment period.	Daily from the day of inclusion to day 5
Treatment compliance	The participant's daily consumption of protein drinks and/or their adherence to a fluid restriction regimen is recorded.	Daily from the day of inclusion to day 5
Quality of life (EQ-5D-5L) questionnaire	Participants' health-related quality of life is assessed using the EuroQol 5 Dimensions, 5 Levels (EQ-5D-5L) questionnaire. , which includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on five levels, ranging from no problems to extreme problems.	On the day of inclusion and on day 5
General well-being	General well-being measured by numerical rating scale (NRS). Score from 0-10 while 10 indicates improved well-being	On the day of inclusion and on day 5

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Mirjam Christ-Crain, Prof. MD, Universitätsspital Basel

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: January 30, 2025
• First Submitted That Met QC Criteria: February 10, 2025
• First Posted (Actual): February 12, 2025

Study Record Updates

• Last Update Posted (Actual): July 10, 2025
• Last Update Submitted That Met QC Criteria: July 7, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: protein supplementation; fluid restriction; dysregulated arginine vasopressin (AVP) secretion; increased renal AVP sensitivity
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Urination Disorders; Urological Manifestations; Disease; Water-Electrolyte Imbalance; Hypothalamic Diseases; Pituitary Diseases; Syndrome; Hyponatremia; Oliguria; Inappropriate ADH Syndrome
• Other Study ID Numbers: 2024-02282; kt25ChristCrain2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No